Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2−/− mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2−/− mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2−/− mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2−/− mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2−/− mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2−/− mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.

中文翻译：

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Nrf2 在衰老过程中红细胞生成中发挥关键作用

衰老的特点是氧化增加和细胞保护机制效率降低。核因子红细胞 2 相关因子 (Nrf2) 是一个关键的转录因子，控制多种抗氧化蛋白的表达。在这里，我们发现 Nrf2−/− 小鼠表现出年龄依赖性贫血，这是由于红细胞寿命缩短和红细胞生成无效的共同作用，表明 Nrf2 在衰老过程中红细胞生物学中的作用。从机制上讲，我们发现衰老过程中抗氧化剂的表达是通过peroxiredoxin-2激活Nrf2功能介导的。 Nrf2 的缺失导致适应性系统的持续氧化和过度激活，例如 Nrf2−/− 小鼠成红细胞中的未折叠蛋白反应 (UPR) 系统和自噬。由于Nrf2参与自噬相关蛋白（例如自噬相关蛋白（Atg）4-5和p62）的表达，我们发现Nrf2−/−小鼠成红细胞的自噬晚期受损。 UPR 系统的过度激活和自噬受损通过 caspase-3 激活驱动 Nrf2−/− 小鼠成红细胞凋亡。作为氧化作用的概念证明，我们用虾青素（一种抗氧化剂）治疗 Nrf2−/− 小鼠，虾青素以聚（乳酸-乙醇酸）（PLGA）负载的纳米粒子（ATS-NP）的形式改善它的生物利用度。 ATS-NPs 改善了 Nrf2−/− 小鼠的年龄依赖性贫血并减少了无效红细胞生成。总之，我们认为 Nrf2 在限制与年龄相关的氧化、确保衰老过程中红细胞的成熟和生长方面发挥着关键作用。